Dysautonomias can result in symptoms in which one or more areas of the body are innervated by the autonomic nervous system. While some dysautonomias are well known, other conditions have yet to be determined as a dysautonomia.
Symptoms of known dysautonomias include: palpitations, chest pain, tachycardia, excessive fatigue, severe fluctuations in blood pressure, excessive sweating, fainting, exercise intolerance, shortness of breath, visual disturbances including blurred vision, tunneling, and double vision, migraines, dizziness, insomnia, gastrointestinal problems including diarrhea, and constipation, bloody stools, fainting/near fainting, frequent urination, convulsions, and cognitive impairment. Secondarily others symptoms such as depression, dysthymia, obsessive compulsive tendencies, and difficulty with ambulation and other symptoms may also be a part of the dysautonomic picture.
Conditions such as familial dysautonomia (FD), also known also as Riley-Day syndrome, Parkinson's disease, Guillaine-Barre syndrome (GBS), Dopamine-b-Hydroxalase deficiency, baroreflex failure, Guillaine-Barre Syndrome, neuroblastoma and other tumors which affect the neuroendocrine system, Aromatic L-Amino Acid Decarboxylase deficiency, Tetrahydrobiopterin deficiency, Familial Paraganglioma syndrome, “Shy-Drager Syndrome,” also referred to as “Multiple System Atrophy” or MSA, Neurally Mediated Syncope, also known as Neurocardiogenic Syncope, diabetic cardiovascular neuropathy, hereditary sensory and autonomic neuropathy type III (HSAN III), Menke's disease, monoamine oxidase deficiency states, and other disorders of dopamine metabolism, dysautonomic syndromes and disorders of the cardiovasular system, Chaga's disease, diabetic autonomic failure, and pure autonomic failure, are well known as conditions associated with or primarily due to a dysautonomia.
Prion diseases are rare. The general worldwide yearly incidence is approximately one case per million people. Thus, in the US, approximately 300 de novo cases of sporadic and genetic prion disease are observed per year. The genetically transmissible forms of prion disease are about one-tenth as common as the sporadic forms. This prevalence is comparable to that observed with the autosomal dominant forms of familial Alzheimer disease and amyotrophic lateral sclerosis (Lou Gehrig's disease).
Prion diseases generally manifest with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs); however, the order and/or predominance of these features and associated neurologic and psychiatric findings vary with prion disease subtype and/or PRNP mutation. The age at onset ranges from the third to ninth decade of life. The course ranges from a few months to several years (typically five to seven years, but in rare cases more than ten years). Death generally results from infection, either by pneumonia (typically from aspiration) or urosepsis. Therapy is aimed at controlling symptoms that may cause discomfort. No cure for prion disease currently exists.
The three phenotypes classically associated with genetic prion disease (fCJD, GSS, and FFI), were defined by clinical and neuropathologic findings long before the molecular basis of this group of disorders was discovered. Although it is now recognized that these three phenotypes are part of a continuum and have overlapping features, it can be helpful to think of genetic human prion disease at least in part in terms of these phenotypes when providing individuals and families with information about the expected clinical course.
Familial Creutzfeldt-Jakob disease (fCJD).
Progressive confusion and memory impairment occur first, followed by ataxia and myoclonus. The disease typically manifests between the ages of 30 and 50 years, although a few individuals present before age 30 or as late as the upper 80s. The course from onset to death ranges from a few months to five years. At the endstage of disease, the individual is generally bedbound, mute, and immobile, except for myoclonic jerks.
The cognitive impairment observed may initially be mild confusion or it may be specific for a particular cortical function, such as language or constructional abilities; however, the resultant picture is one of global dementia. As the disease progresses, neurobehavioral symptoms may vary considerably. Psychiatric features, including delusions and hallucinations, may also occur.
Ataxia may be either truncal or appendicular, manifesting either as an unsteady gait, clumsiness while carrying out commonly performed tasks (e.g., picking up the salt shaker while dining), or progressive dysarthria. As the ataxia progresses, the individual may fall repeatedly, necessitating the use of a wheelchair to prevent injury.
Myoclonus generally, but not always, occurs after cognitive impairment is evident. Myoclonus may begin focally in a single limb but eventually becomes generalized. “Startle myoclonus” may be elicited by simple acts such as clapping the hands or turning on the room lights. Even if warned of an impending noise, the individual cannot suppress the startle response.
Other neurologic signs and symptoms such as focal or generalized weakness, rigidity, bradykinesia, tremor, chorea, alien hand syndrome, stroke-like symptoms, visual disturbances, and seizures have been observed.
Gerstmann-Sträussler-Scheinker syndrome (GSS).
GSS typically begins in the fourth to sixth decade with the insidious onset of cerebellar dysfunction, manifest as unsteady gait and mild dysarthria. Cognitive dysfunction is generally not apparent early on; however, with progression, bradyphrenia, or slowness of thought processing, may become evident. Pyramidal involvement with spasticity and/or extrapyramidal involvement with bradykinesia, increased muscle tone with or without cogwheeling, and masked facies are also common. Psychiatric or behavioral symptoms are atypical. The disease progresses at a relatively slow but relentless pace over the course of a few to seven or more years. Cerebellar dysfunction results in severe dysarthria, gait and appendicular ataxia, ocular dysmetria, and lack of coordination in swallowing. A decline in cognitive abilities, particularly of concentration and focus, becomes apparent with progression into the late stage of disease. In the terminal stage, the individual is bedridden from the disabling ataxia, unable to eat because of severe lack of coordination in swallowing, and unable to communicate because of the profound dysarthria; yet insight into his/her condition may remain. This pattern of progression relates to the cerebellar nature of this disease, with progression into the brain stem and eventually the cerebrum.
Fatal Familial Insomnia (FFI).
FFI typically presents in midlife (40s to 50s) with the insidious or subacute onset of insomnia, initially manifest as a mild, then more severe, reduction in overall sleep time. When sleep is achieved, vivid dreams are common. A disturbance in autonomic function then emerges, which may manifest as elevated blood pressure, episodic hyperventilation, excessive lacrimation, sexual and urinary tract dysfunction, and/or a change in basal body temperature. Signs of brainstem involvement, such as decreased ability to gaze upward, double vision, jerky eye pursuit movements, or dysarthric speech may also appear in some individuals. With continued progression over the next few months, individuals develop truncal and/or appendicular ataxia. The speed of thought processing may be reduced, as is common in subcortical dementing states, and memory impairment may be variable; however, compared with other more prominent features of disease, cognitive capacity is relatively spared until late in the course. Advancing disease results in progressively greater loss of total sleep time, worsening ataxia, and more profound confusion, leading ultimately to an awake but stuporous state as death approaches. As with other forms of prion disease, debilitation leading to feeding difficulties and loss of airway protection is the most common immediate cause of death. The typical duration of disease is 12 to 16 months, with a range of a few months to five years.
Other Prion Diseases.
About 10-15% of prion diseases are genetically transmissible, while the remainder occur from unknown risk factors or are acquired through infection with prions; these include sporadic Creutzfeldt-Jakob disease (sCJD), iatrogenic CJD (iCJD), variant CJD (vCJD), and sporadic fatal insomnia (sFI). Kuru, a prion disease associated with the practice of cannibalism in a primitive culture in New Guinea, is primarily of historical significance.
sCJD.
The clinical and pathologic features of sCJD are the same as fCJD; however, the duration of disease is typically much shorter, on the average of six months or less, and the age at onset is later, typically after age 60 years.
sFI.
The phenotype is the same as in FFI, including age at onset and duration of disease. sFI is much less common than FFI.
iCJD.
Diagnosis of this form of prion disease requires the identification or strong association with administration of a biological extract or tissue contaminated with prions. Such sources have included injections of human growth hormone contaminated with prions (used prior to 1980), improperly decontaminated depth electrodes previously used in individuals with CJD, transplantation of corneas obtained from individuals with CJD, dura mater grafts contaminated with prions, and various poorly documented neurosurgical procedures.
vCJD.
This prion disease represents a relatively new strain of CJD acquired by ingestion of beef or beef products contaminated with bovine spongiform encephalopathy (BSE), the prion disease of cattle (commonly known as mad cow disease). The typical clinical picture is that of a young adult or teen who develops behavioral changes and/or pain in the lower extremities that eventually lead to a progressive dementia with ataxia and myoclonus. The course is about 1.5 years. The EEG is often diffusively slow rather than periodic, and the 14-3-3 CSF protein test is more often negative than positive. Neuropathology reveals spongiform change spread diffusely throughout the brain and dense amyloid plaque deposition surrounded by a halo of vacuolation described as “florid plaques.